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Title: Palladium-catalyzed direct regioselective C-H acylation of oximes and anilides and copper-catalyzed trichloromethylation of N-aryl-acrylamides
Authors: Chan, Chun Wo
Degree: Ph.D.
Issue Date: 2015
Abstract: Palladium-catalyzed ortho-selective arene CH functionalizations are promising approach for developing sustainable organic synthesis. Most successful examples involve alkenes/alkynes and organometallic reagents for CC bond formation. This thesis explores the catalytic coupling of arenes with aldehydes and chloroform for regioselective CC bond formation. Our study showed the principal step involves transforming the aldehydes and chloroform to carboradicals, which are key intermediates for the coupling reactions. To begin, direct acylation of acetophenones with aldehydes to afford 1,2-diacylbenzenes was examined. Treating acetophenone O-methyloxime with 4-chlorobenzaldehyde (2a), TBHP and Pd(OAc)₂ (5 mol%) in toluene at 100 °C furnished the desired benzophenone (3a) in 71% yield. This acylation reaction exhibits excellent ortho-selectivity; functional groups such as methoxy, sulfonyl, halogen and amide were tolerated. Apart from benzaldehyde, aliphatic and heteroaromatic aldehydes are also effective partners with 55-95% product yields being achieved. In this work, 3a was deoximinated to give diketone (4a) which was converted to phthalazines - a medicinally useful heterocycle. The related ortho-selective acylation of anilides was examined for synthesis of 2-aminobenzophenones. Treating N-pivalanilides (6a) with 4-chlorobenzaldehyde, TBHP, TFA (1 equiv) and Pd(OAc)₂ (5 mol%) in toluene at 40 °C for 3 h, produced the corresponding ortho-acylated anilide in 80% yield. This anilide acylation also displayed excellent ortho-selectivity and functional group tolerance for a wide range of substrates. For example, aldehydes containing heteroaromatic rings and strained cyclopropanes have been successfully coupled to anilides.
Kinetic study on the acylation of 2-phenylpyridine (8a) with 4-chlorobenzaldehyde (2a) with TBHP revealed an experimental rate law : rate = k[8a]-1[Pd]². The inverse first-order dependence of [8a] suggests that the turnover-limiting step should involve substrate dissociation. The second-order dependence on [Pd] suggests the involvement of dinuclear palladium complex in the turnover-limiting step. With 8a-d5 as substrate, significant primary kinetic isotope effect (kH / kD = 5.6) is consistent with substantial CH bond cleavage at the turnover-limiting step. A Hammett correlation study on a series of meta-substituted pivalanilides (6) (Y = OMe, Me, Ph, H, Cl and Br) revealed a linear free energy relationship (R = 0.96) and small ρ⁺ value of -0.74. The small negative ρ⁺ value implies that the Pd(II)-mediated CH cleavage should not proceed through an cationic arene intermediate. Reacting the cyclopalladated complex [Pd(C~N)(OAc)]₂ (C~N = 2-phenylpyridine) (8a-Pd) with 2a (3 equiv) and TBHP (2 equiv) afforded the coupled ketone in 42% yield. The catalytic CH acylation was suppressed by radical scavengers such as ascorbic acid in a dose-dependent manner. When 2,2,6,6-tetramethylpiperidine N-oxide (TEMPO) (1 equiv) was employed as additives, the ketones formation was completely suppressed and the 2,2,6,6-tetramethylpiperidino-4-chlorobenzoate was isolated in 78% yield. These finding are compatible to intermediacy of carboradicals in the acylation reaction. The catalytic acylation is probably mediated by coupling of the carboradicals with the arylpalladium(II) complexes. Trichloromethyl moiety is prevalent to many medicinally useful molecules such as dysamide, barbamide and muironolide. In this work, we examined trichloromethyl [CCl3] radical generated from chloroform for CH coupling reactions. Treating cyclopalladated complex 8a-Pd with di-tert-butylperoxide in chloroform at 120 °C failed to afford any trichloromethylated arenes. However, treating N-arylacrylamides (1 equiv) with di-tert-butylperoxide in chloroform in 120 °C furnished the carbocyclized 2-oxindoles (10a) in 68% yield. In the presence of CuBr₂ (5 mol%), this reaction proceeded to give the 2-oxindole up to 87% yield. Functional groups such as methoxy, halogen and ketone groups are well tolerated.
Subjects: Palladium catalysts.
Organic compounds -- Synthesis.
Hong Kong Polytechnic University -- Dissertations
Pages: xxix (incomplete), 391 pages : illustrations (some color)
Appears in Collections:Thesis

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